(1) Field of the Invention
The present invention relates to inhibitors of the enzyme matrix metalloproteinase-13 (“MMP-13”), pharmaceutical compositions comprising said inhibitors, and methods of treating diseases responsive to inhibition of MMP-13 comprising administering said inhibitors. The preceding statement is meant to be illustrative of the field of the invention only, and should not be construed to limit the scope of the present invention, which is fully, clearly, concisely, and exactly described below.
(2) Description of the Related Art
Matrix metalloproteinases (sometimes referred to as “MMPs”) are naturally-occurring (i.e., endogenous) enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and natural endogenous tissue inhibitors of MMPs (sometimes referred to as “TIMPs”) have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinase (“MMP”) family. Other members of the MMP family include fibroblast collagenase (“MMP-1”), neutrophil collagenase (“MMP-8”), gelatinase B (“92 kDa gelatinase” or “MMP-9”), stromelysin-2 (“MMP-10”), stromelysin-3 (“MMP-11”), matrilysin (“MMP-7”), collagenase-3 (“MMP-13”), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65). Overactivity of these enzymes has been implicated in a number of diseases which result from breakdown of connective tissue or extracellular matrix, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, stroke, renal disease, macular degeneration, and tumor metastasis. Inhibition of MMPs is now a recognized method for preventing and treating these diseases and other diseases responsive to inhibition of MMPs, as MMP inhibitors curtail and/or eliminate the breakdown of connective tissues or extracellular matrices that is intrinsic to these disease states.
MMPs contain a catalytic zinc cation that typically must coordinate to a functional group in a substrate before cleavage of the substrate by the MMP can occur. This catalytic zinc is usually the focal point for inhibitor design. For example, the modification of substrate mimics by introducing zinc-chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and TIMPs have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, as described in U.S. Pat. No. 5,948,780.
A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular MMP enzyme. Further, recent studies have shown that MMP inhibitors also inhibit the production of tumor necrosis factor alpha (“TNF-α”) by inhibiting TNF-α converting enzyme (“TACE”), which is also known as TNF-α convertase. Recent data has established that specific MMP enzymes are associated with some diseases, but are not associated with others. A nonselective inhibitor of MMPs may potentially inhibit MMPs that are not involved in the process of the particular disease being treated, thereby “diluting” the inhibitor's effectiveness and, further, possibly leading to undesirable side effects in vivo.
The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 preferentially cleave native interstitial collagens, and thus usually are associated only with diseases linked to such interstitial collagen tissue. Nevertheless, it seems some diseases may involve overactivity of only one MMP. This is indicated by the recent discovery that MMP-13 alone is over expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Am. Chem. Soc., 2000;122:9648-9654).
A selective inhibitor of MMP-13 would thus be valuable. However, there appears to be only one highly selective inhibitor of MMP-13, namely WAY-170523 reported by Chen et al., Supra., 2000. The need continues to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency, which makes them amenable for use clinically in the prevention and treatment of the associated disease states.
One aspect of the present invention is a group of MMP-13 inhibitor compounds characterized as being diacid-substituted heteroaryl derivatives. A further aspect of this invention is MMP-13 inhibitor compounds that are selective inhibitors of MMP-13. All that is needed to practice the invention is to administer from 1 to 6 times daily to a patient in need of treatment, a therapeutically effective amount of a compound of the invention. Determination of dosage forms, amounts of a compound to administer, routes of administration, and identification of patients in need of treatment is discussed below and is within the average skill in veterinary or medical arts.
The preceding description is for background purposes only, and is not to be construed, in part or in whole, as an admission of prior art.